Complement and neutrophils are actively involved at the cervicovaginal interface in cases of adverse microbial composition, cervical shortening and spontaneous preterm birth.

Microbial-driven spontaneous preterm birth (sPTB) is linked to adverse vaginal microbiome and dysregulated immune responses, yet this knowledge has not translated into predictive tools or therapies. We sampled 186 high-risk pregnant women and assessed 14 complement proteins and the neutrophil immunophenotype at the cervicovaginal interface to expand potential targets. Alterations in classical and alternative complement pathway components were associated with bacterial community composition and preceded cervical shortening and sPTB. At 12+0-16+6 weeks, women with Community State Type (CST) IV had significantly higher concentrations of C1q, C4, C4b, Factor B, D, C3b/iC3b, and Factor H, I than those with CST I. Women who later developed a short cervix and delivered preterm showed lower L. crispatus abundance and elevated complement activation. Neutrophils were the dominant local immune cell and exhibited enhanced activation relative to peripheral neutrophils, with altered expression of CD11b, CD62L, CD63 and CD66b. Cervical neutrophil CD63, CD66b, and CD88 differed between CST IV and CST I, though not by pregnancy outcome. Neutrophil abundance correlated with cytokines, complement proteins, and MMPs, suggesting roles in inflammation and tissue remodelling. These findings highlight a microbiota-driven complement-neutrophil axis present before cervical remodelling and sPTB, identifying potential complement-based predictors and therapeutic targets.